The use of antiviral agents within the first 72 hours of the onset of the rash of herpes zoster can reduce the duration of the rash and the duration of postherpetic neuralgia^15-18. The antiviral agents acyclovir, valacyclovir, and famcyclovir are highly selective for thymidine kinase, an enzyme encoded by the herpes zoster virus, and ultimately inhibit viral replication. By inhibiting viral replication, the duration of viral shedding and lesion formation, the time to rash healing, the severity and duration of acute pain from zoster, and the risk for progression to postherpetic neuralgia are reduced. Acyclovir (800mg po 5 times daily for 7-10 days), valacyclovir (1 gm po tid for 7 days), and famcyclovir (500 mg po tid for 7 days) can cause the following side-effects: nausea, vomiting, diarrhea, abdominal pain, and headache. A meta-analysis of four double-blind, randomized, placebo-controlled trials of oral acyclovir for herpes zoster demonstrated an acceleration in the resolution of zoster-associated pain and a reduction by at least 50% in the prevalence of postherpetic neuralgia at 3 and 6 months in patients who received

acyclovir¹⁵. These benefits of acyclovir therapy were greatest for patients 50 years of age or older¹⁵. Valacyclovir accelerated the resolution of herpes zoster-associated pain and postherpetic neuralgia, reduced the proportion of patients with pain persisting for at least 6 months¹⁶ .Valacyclovir reduces the duration of pain (51 days with acyclovir vs. 38 days with valacyclovir) and reduces the pain at 6 months (26% of patients taking acyclovir vs. 19% of patients taking valacyclovir) more than acyclovir¹⁶ . In a double-blind, randomized comparison of valacyclovir and high dose famcyclovir in acute herpes zoster, valacyclovir treatment is comparable to famcyclovir treatment in speeding the resolution of zoster associated pain and postherpetic neuralgia¹⁷. Postherpetic neuralgia resolves two times faster in patients taking famcyclovir than those receiving the placebo with a 3.5 month reduction in the average duration of pain¹⁸ .

Therefore, the antiviral agents acyclovir, valacyclovir, and famcyclovir reduce the duration of the rash and the duration of postherpetic neuralgia^15-18 Valacyclovir reduces the duration of pain and reduces the pain at 6 months more than acyclovir¹⁶. Valacyclovir treatment is comparable to famcyclovir treatment in speeding the resolution of zoster associated pain and postherpetic neuralgia¹⁷.

Gabapentin, an anticonvulsant, has been used to treat neuropathic pain. In a multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial, gabapentin (titrated to a maximum of 3600mg/day) significantly reduced postherpetic neuralgia pain (a reduction in mean daily pain score from 6.3 to 4.2 with gabapentin vs. a reduction with placebo from 6.5 to 6) and associated sleep disturbance with an improvement in mood and quality of life¹⁹ . Yet, the patients in this study who received gabapentin had side effects occurring at higher incidences than in the placebo group such as somnolence, dizziness, ataxia, peripheral edema, and infection¹⁹. In a multicentre, double-blind, randomized, placebo controlled 7-week study, gabapentin (1800 and 2400 mg/day) significantly reduced postherpetic neuralgia pain with the most common side effects of dizziness and somnolence²⁰. Although there is no standard dosing regimen, treatment can be initiated at 900mg/day (300mg po day 1, 300mg po bid day 2, 300mg po tid day 3) with an additional titration to 1800mg/day for additional efficacy as tolerated²¹. Some patients may require doses up to 3600mg/day²¹. Dosage adjustment in patients with renal insufficiency is necessary. The mechanism of analgesic action of gabapentin is unclear. Most likely, gabapentin binds to the alpha₂ -delta₁ subunit of voltage-gated calcium channels decreasing calcium influx, and inhibiting the release of excitatory neurotransmitters²² and also acts directly in the brainstem via a glutamate-dependent mechanism to stimulate descending inhibition to produce antihypersensitivity after peripheral nerve injury²³.

Pregabalin, an anticonvulsant, also has been used to treat neuropathic pain. In a multicenter, parallel-group, double-blind, placebo-controlled, 8-week, randomized clinical trial, pregabalin (600mg/day or 300mg/day based on renal clearance) significantly reduced postherpetic pain beginning the first day of treatment (50% of patients treated with pregabalin and 20% of patients treated with placebo had equal to or greater than 50% decrease in their pain) and improved sleep in patients with postherpetic neuralgia beginning the end of the first week of treatment²⁴. Dizziness and somnolence were the most significant side effects of pregabalin treatment in this study²⁴. In a randomized, double-blind, multicentre, placebo-controlled, parallel-group design to evaluate the efficacy and safety of twice a day flexible (15-600 mg/day) or fixed-dose (600mg/day) pregabalin in patients with postherpetic neuralgia or diabetic neuropathy, a significant reduction of pain and improvement in sleep over placebo was demonstrated²⁵. In a 4-week randomized trial comparing flexibly-dosed pregabalin (150-600mg/day), fixed-dose pregabalin (300mg/day), and placebo, pregabalin fixed- and flexible-dose regimens produced significant reductions in pain in 1.5 and 3.5 days respectively in patients with postherpetic neuralgia and a reduction in allodynia after one week²⁶. Discontinuation rates due to adverse events were more frequent in the fixed-dose group ²⁶. In another randomized, double-blind, multicentre, placebo-controlled trial, pregabalin was also shown to significantly reduce pain, improve sleep, mood disturbances, and health-related quality of life measures in patients with postherpetic neuralgia²⁷.

Pregabalin, like gabapentin, binds to the alpha₂ -delta₁ subunit of voltage-gated calcium channels decreasing calcium influx, and inhibiting the release of excitatory neurotransmitters²².

Pregabalin binds to the alpha₂ -delta₁ subunit with six times greater affinity than gabapentin²⁸. Both gabapentin and pregabalin have a high correlation between plasma clearance and renal function, similar elimination half-lives, no inhibition of the cytochrome P450 enzymes, minimal drug-drug interactions, and a similar adverse effect profile. Pregabalin, however, has a higher bioavailability independent of dose (90% with pregabalin versus 33-66% with gabapentin which is saturable and dose-dependent), is rapidly absorbed (peaks one hour versus 3-4 hours with gabapentin), increases its plasma concentrations linearly with increasing doses, and has low intersubject pharmacokinetic variability²⁹. In a retrospective study, patients with postherpetic neuralgia in the usual-care setting, there was increased opioid use after the initiation of gabapentin and decreased opioid use after the initiation of pregabalin³⁰.

In summary, both gabapentin and pregabalin significantly reduce postherpetic neuralgia pain, associated sleep disturbance with an improvement in mood and quality of life^19,27. ^{Pregabalin, however, has a higher bioavailability independent of dose, is rapidly absorbed, increases its plasma concentrations linearly with increasing doses, and has low}

intersubject pharmacokinetic variability²⁹. Both a fixed- and flexible-dose of pregabalin regimen appear to be effective²⁶. When opioids are combined with gabapentin or pregabalin, there was increased opioid use after the initiation of gabapentin and decreased opioid use after the initiation of pregabalin³⁰.

In a randomized, double-blind, parallel design trial comparing desipramine (titrated to a maximum dose of 150mg/day), amitriptyline (titrated to a maximum dose of 150mg/day, and fluoxetine (titrated to a maximum of 60mg/day) in patients with postherpetic neuralgia, all three agents reduced daily diary pain or end-treatment pain relief category with desipramine producing relief in 80% of those treated³¹. Adding fluphenazine to amitriptyline does not significantly provide more pain relief than amitriptyline alone³². Tricyclic antidepressants, such as desipramine and amitriptyline, inhibit the reuptake of norepinephrine and serotonin³³, block N-methyl-D-aspartate (NMDA) receptors ³⁴, block sodium channels^35,36, and block calcium channels³⁷. The selective serotonin reuptake inhibitors (SSRIs) inhibit serotonin reuptake without action on noradrenaline reuptake³³. Fluoxetine blocks sodium channels, unlike other SSRIs, yet the blockade seems to be different than that of tricyclic antidepressants³⁶ . Side effects of tricyclic antidepressants include dry mouth, sweating, dizziness, orthostatic hypotension, fatigue, constipation,

problems with micturition, and cardiac disturbances. The SSRI’s may cause nausea, vomiting, and dyspepsia. Of interest, topical use of tricyclic antidepressants has been studied. In a randomized, placebo-controlled crossover study in the study of neuropathic pain, topical 5% amitriptyline and 5% lidocaine were compared showing that topical 5% lidocaine reduced pain intensity and topical 5% amitriptyline was not effective in reducing pain intensity³⁸. Furthermore, a randomized trial of patients (>60 years of age) diagnosed with herpes zoster initiated 25mg of amitriptyline or placebo within 48 hours of rash onset and continued the treatment for 90 days³⁹. The amitriptyline group, in this study, showed a 50% decrease in pain prevalence at 6 months³⁹.

In summary, desipramine, amitriptyline, and fluoxetine reduced the pain in patients with postherpetic neuralgia, with desipramine producing relief in 80% of those treated treated³¹. Adding fluphenazine to amitriptyline does not significantly provide more pain relief than amitriptyline alone³². Furthermore, topical 5% amitriptyline was not effective in decreasing neuropathic pain³⁸.

The 5% lidocaine patch relieves the pain and allodynia of patients with postherpetic neuralgia⁴⁰. The patch is a topical adhesive patch containing 700 mg of lidocaine and up

to three patches can be applied simultaneously for 12 hours per day. One to three patches or a portion of a patch can be placed over the painful area⁴¹. The mechanism of the patch is believed to be the reduction of aberrant firing of sodium channels on damaged pain nerve fibers directly under the patch⁴¹. Systemic lidocaine levels remain well within a safe range with doses of up to 4 patches on for 24 hours⁴¹. Adverse reactions are rare, mild, and mostly topical⁴¹. The lidocaine patch is contraindicated in advanced liver failure because of the decreased metabolism of lidocaine⁴¹. In a prospective, randomized, placebo-controlled, two-way, cross-over study in three medical hospitals, the topical application of 5% lidocaine patch effectively relieved pain and allodynia in postherpetic neuralgia patients⁴². A cost comparison study in the United States found that, on average, patients receiving the lidocaine patch spent $1780 per patient-year less on health care than patients receiving branded gabapentin as an analgesic and spent $1330 less than those receiving generic gabapentin⁴³. So, 5% lidocaine patch is effective on relieving the pain and allodynia of patients with postherpetic neuralgia⁴⁰.

As another treatment for postherpetic neuralgia, capsaicin is an agonist at transient receptor potential vanilloid 1 which is present on primary nociceptive afferent terminals.

Topical capsaicin cream (0.075%), as a treatment for postherpetic neuralgia, statistically improved the number of patients experiencing pain relief versus placebo^44,45. In these studies, 0.075% capsaicin cream was applied four times daily and the main side effect, burning or stinging, diminished after the first week^44,45.

Opioid analgesics have been used for the treatment of nociceptive and cancer pain, yet their role in the management of nonmalignant neuropathic pain, such as postherpetic neuralgia, has been controversial. Also, other factors, such as opioid-related side effects, development of tolerance, and fear of addiction contribute to the controversy of using opioids for the treatment of nonmalignant neuropathic pain. Despite these controversies, studies demonstrate the effectiveness of opioids in the treatment of neuropathic pain, particularly postherpetic neuralgia^46-49. In a double-blind, placebo-controlled, randomized, controlled trial, intravenous infusions of morphine or lidocaine provided significant pain relief in patients with postherpetic neuralgia⁴⁶. In the majority of subjects who reported pain relief, allodynia also disappeared⁴⁶. ^{In a double-blind, placebo-controlled, randomized trial, controlled-release oxycodone (titrated to a maximum dosage of 60mg per day) provided significant benefits with respect to pain, disability, and allodynia compared with placebo47. Controlled-released oxycodone demonstrated rapid}

onset of pain control, superior efficacy in relieving both moderate and severe postherpetic neuralgia pain, a good safety profile, and a decrease in the concomitant use of three-ladder analgesics⁴⁸. In a double-blind , placebo-controlled, randomized three-period crossover study, treatment with oral morphine (mean daily dose 91mg), tricyclic antidepressants (mean daily dose nortriptyline 89mg and desipramine 63mg), and placebo in patients with postherpetic neuralgia were compared⁴⁹. The efficacy of opioids and tricyclic antidepressants for pain relief were similar and more than placebo, yet the patients preferred treatment with opioid analgesics, despite a greater incidence of side effects during opioid treatment⁴⁹. In a double-blind dose-response trial, a postherpetic neuralgia subgroup examining the use of opioids (levorphanol)for the treatment of neuropathic pain showed a greater reduction in pain with higher doses rather than lower doses of opioids⁵⁰ . Despite receiving 12 months of treatment with oral morphine for chronic non-cancer pain, patients in a long-term prospective study did not demonstrate impairment in neuropsychological tests⁵¹. The most common side effects of opioid analgesic therapy include constipation, sedation, and nausea. Opioid analgesics must be used cautiously in patients with a history of substance abuse.

In summary, in terms of the use of opioids for the treatment of postherpetic neuralgia, both intravenous and oral administration of opiods have been shown to provide significant relief of pain and allodynia^46,47. Higher doses rather than lower doses of

0pioids provided a greater reduction of pain in patients being treated for neuropathic pain⁵⁰. Finally, despite patients receiving long-term treatment with oral morphine, there was not an impairment noted in neuropsychological testing⁵¹.

The analgesic actions of tramadol are mediated by its opioid agonist activity at the mu receptor and the inhibition of the reuptake of norepinephrine and serotonin. In a multicenter, randomized, double-blind, parallel-group study, six weeks of treatment with

tramadol (100-400mg/day) for postherpetic neuralgia was associated with a reduction in pain ⁵² .

Interventional treatment options for postherpetic neuralgia have been examined as potential treatments of postherpetic neuralgia. These treatment options include sympathetic blocks, epidural and intrathecal methylprednisolone, and spinal cord stimulators.

Sympathetic nerve blocks have been utilized as a treatment modality in patients with postherpetic neuralgia. In studies evaluating the effectiveness of sympathetic nerve blocks in treating postherpetic neuralgia and preventing postherpetic neuralgia, there are significant methodological issues which effect the evaluation of the role of sympathetic blocks in postherpetic neuralgia⁵³. These methodological issues include lack of control groups, varying definitions of postherpetic neuralgia, inadequate assessments of pain severity and relief, lack of appropriate follow up, adequate sample size, and lack of double-blind, randomized, controlled trials⁵³. Sympathetic blocks may be effective in relieving pain during acute herpes zoster, yet they do not seem to provide long term relief in patients in patients with long-standing postherpetic neuralgia^54,55. If sympathetic blocks reduce the severity of the acute pain, a risk factor for increasing the development of postherpetic neuralgia⁹, then they may theoretically prevent the development of postherpetic neuralgia.

Patients who have had postherpetic neuralgia have inflammation around the spinal cord with infiltration and accumulation of lymphocytes² and high concentrations of interleukin-8 in the cerebrospinal fluid⁵⁶ . Patients with intractable postherpetic neuralgia for at least one year, in a randomized, controlled study, revealed that an intrathecal

injection of methylprednisolone and lidocaine (versus lidocaine alone or no treatment) significantly decreased pain, the area of pain, the use of diclofenac (by 70% 4 weeks at the end of treatment), and allodynia⁵⁷ . In the intrathecal methylprednisolone and lidocaine group, the cerebrospinal fluid (CSF) concentration of interleukin-8 decreased by 50% and this decrease correlated with the duration of neuralgia before treatment and with global pain relief ⁵⁷. Intrathecal administration of methylprednisolone appears to provide greater relief and lower CSF levels of interleukin-8 compared to epidural methylprednisolone⁵⁶. Additional studies are needed to determine the safety of intrathecal methylprednisolone since it has been associated with neurological complications such as arachnoiditis^57,58,59.

Spinal cord stimulation is an interventional treatment option for some types of neuropathic pain⁶⁰. For patients with postherpetic neuralgia with pain more than two years duration with preserved sensory function refractory to conventional pharmacotherapy, spinal cord stimulation provided 82% of the patients with long-term relief⁶¹ .The mechanism of spinal cord stimulation is unclear. Postulated mechanisms include the stimulation of large myelinated A-beta fibers interfering with the transmission

of nociceptive information carried by small unmyelinated C and myelinated A-delta fibers from the periphery, suppression of sympathetic overdrive, and inhibition of nociceptive processing via GABA-ergic interneurons^60,61.